Parkinson's disease (PD) primarily results from a substantial loss of dopaminergic neurons in the midbrain. Despite extensive studies, the mechanisms underlying the neuron death in PD remain unknown. A limited understanding on the disease mechanisms is a major roadblock in the development of PD therapy. Dopamine as the specified neurotransmitter has long been suspected as a potential determinant of neurodegeneration in PD. In the dopaminergic neurons, free dopamine in the cytosol is a unique source of endogenous toxins leading to neuron death;however, dopamine of physiological concentration is not sufficient to cause cell death. Dopamine may become toxic when other risk factors coexist. Aging is a high risk factor for PD. Physiological changes during the aging may compromise cell protection machinery, increasing the sensitivity of dopaminergic neurons to chronic dopamine toxicity. While most PD cases are sporadic, about 10% of the cases are caused by pathogenic mutations in individual genes. While pathogenic mutations in the alpha-synuclein or the LRRK2 gene gain toxic properties, mutations in the neuron-protective genes (i.e. parkin, DJ-1 and PINK1) abolish protective effects of the genes. How these disease genes play their roles in sporadic PD remains to be elucidated. In PD, dopaminergic neuron death might be a final accumulative effect of multiple risky factors such as chronic dopamine toxicity, physiological changes during aging, gain of toxic properties for neurotoxic genes, or loss of protective functions for neuron-protective genes. To test proposed mechanisms of dopaminergic neuron death in PD, we have created two novel mouse lines: DAT-CreERT2 transgenic mouse and conditional VMAT2 knockout mouse. With the existing novel mouse models, we will assess the enhancing effect of aging on chronic dopamine toxicity and assess the accumulative adverse effect of chronic dopamine toxicity and mutations in the alpha-synuclein on dopaminergic cell survival in compound mouse models. The results from these studies would advance the understanding on the disease mechanisms and would guide the development of PD therapy.